Recent research suggests (Baron-Cohen et al., 2009; Schechter and Grether, 2008; Thomas et al., 2011; Zaroff and Uhm, 2011) that approximately 0.6-1.5% of the general population may be diagnosed as having Autism or Autism Spectrum Disorder (thereafter “ASD”), which are neurodevelopmental disorders that are distinguished and characterized by deficits in social reciprocity, communication impairments, and restricted, repetitive interests and behaviors (World Health Organization, 1993). Other symptoms, such as atypical eating, are common in autistic children. In addition, symptoms for ASD, as defined in the DSM-V, are likely present in early childhood and collectively limit and hinder everyday functioning.
For instance, patients of severe Asperger's Syndrome, one of the Autism Spectrum Disorders can have one or more of the following primary symptoms:                Extreme difficulty with social interaction        Inability to have metered speech        Difficulty making conversation        Inability to make eye contact        Profound need to conform to a rigid schedule and great difficulty deviating from it        Difficulty with information processing        Sensitivity to novel stimuli        Difficulty bonding        Anxiety        Hypersensitivity to touch        Difficulty transitioning        Difficulty multitasking        Severe ruminations        Severe obsessional thoughts and actions        Fixations        Severe perseveration        Seizures        Hypergraphia        Jamai vu' and deja vu'        
In particular, ASD patients report experiencing continuous pain, which has been described by some as “psychic/phantom” pain (i.e., severe and extremely debilitating pain that is neither physical nor emotional). Some studies of ASD patients have pointed to the potential underlying cause as ASD patients having, inter alia, an amplified pain sensitivity and/or observer perception of pain. More discussions of ASD-related pain can be found in the literature: see e.g., Allely (2013), Moore (2015) and Clarke (2015).
Past and the Present Methods of Autism Treatments
Therapies for treatment of autism include conventional, intensive Applied Behavioral Analysis (ABA) therapy as well as a host of alternative approaches, including a gluten-free and casein-free (GFCF) diet, hyperbaric oxygen chambers, chelation, aroma therapies, electro-magnetics, spoons rubbed on his body, multivitamin therapy, B-12 shots and a range of prescription psychosomatic drugs.
In spite of the prior research and the knowledge, nonetheless, there is no cure for autism, but a number of therapeutic agents developed for other conditions have been found to be, to some extent, helpful in treating a limited number of the symptoms and behavioral problems. Examples of such therapeutic agents used to treat symptoms associated with autism (such as hyperactivity, impulsivity, attention difficulties, and anxiety) include: serotonin re-uptake inhibitors (e.g. clomipramine (Anafranil), fluvoxamine (Luvox) and fluoxetine (Prozac)). Studies show that they reduce the frequency and intensity of repetitive behaviors, decrease irritability, tantrums and aggressive behavior, improvements in eye contact and responsiveness. Other drugs, such as Elavil, Wellbutrin, Valium, Ativan and Xanax, are also being tried to decrease the behavioral symptoms.
The extensively studied psychopharmacologic agents in ASD have been anti-psychotic medications developed for treating schizophrenia. These therapeutic agents do decrease hyperactivity, stereotypic behaviors, withdrawal and aggression in autistic children. Four anti-psychotic medications that have been approved by the FDA are clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa) and quetiapine (Seroquel). However, only risperidone has been investigated in a controlled study of adults with autism. Stimulants, such as Ritalin, Adderall, and Dexedine, used to treat hyperactivity in children with ADHD have also been prescribed for children with autism. They are said to increase focus, and decrease impulsivity and hyperactivity in autism; regrettably, adverse behavioral side effects are often observed.
US Patent Application No. 2009/0048348 A1 by M. Chez disclosed that administering effective doses of a NMDA-receptor antagonist or a pharmaceutically acceptable salt thereof improves frontal executive functions associated with autistic symptoms, including, but not limited to, speech expression and decreased perseveration without any side effects associated.
Currently, autism spectrum disorders are treated by using: inter alia, applied behavior analysis or other behavior modification techniques; dietary alteration (e.g., a gluten or casein free diet); large doses of vitamin B6 in combined with magnesium; medications specific symptoms (e.g., anxiety and depression) and include agents (e.g., fiuoxetine, fiuvoxamine, sertraline and clomipramine); and, antipsychotic medications (e.g., chlorpromazine, thioridazine, and haloperidol) have been used to treat behavioral problems. Anticonvulsants (e.g., arbamazepine, lamotrigine, topiramate, and valproic acid) have been given to prevent seizures.
Numerous studies have reported differences in brain anatomy and function in individuals with ASD (See e.g., Craig et al., 2007; Ecker et al., 2010; Hallahan et al., 2009), but the underlying molecular basis of the disease condition remains unclear. ASD is now viewed as a heterogeneous set of disorders, which can be caused by various genetic, epigenetic and environmental factors, but emerging evidence suggests that an imbalance between excitatory glutamate and inhibitory gamma-amino-butyric-acid (GABA) neurotransmission may form a final common pathway in ASD.
In particular, defects in GABA transmission, leading to brain hyperexcitability, have been hypothesized to underlie the symptoms of ASD (Pizzarelli and Cherubini, 2011; Rubenstein and Merzenich, 2003; Yizhar et al., 2011). GABAA receptors (GABAA R) are pentameric assemblies from a pool of different subunits (α1-α6, β1-3, γ1-3, δ, ε, π, θ) that form a Cl-permeable channel that is gated by the neurotransmitter γ-aminobutyric acid (GABA). Various pharmacological effects, including anxiety disorders, epilepsy, insomnia, pre-anesthetic sedation, and muscle relaxation, are mediated by different GABAA subtypes. More specifically, GABA receptor genes have been associated with autism in linkage and copy number variation studies. Fewer GABA receptor subunits have been observed in the post-mortem tissue of autistic individuals. Further, it's been shown that neurotransmitter GABA signaling is disrupted across heterogeneous mouse models of autism.
US Patent Application No. 2015/0313913 A1 by W. A. Catterall, entitled “Positive allosteric modulators of the GABAA receptor in the treatment of autism,” provided various methods and formulations for treating an Autism Spectrum Disorder using low doses of an agent that enhances signaling through the GABA receptor. These included α2 and/or α3 selective GABAA receptor positive allosteric modulators, but specifically avoided targeting α1 GABAA receptors.
US Patent Application No. 2010/0136004 A1 by L. Mei et al, provided methods and compositions for modulating GABA release in a subject are provided. A preferred embodiment provides a composition containing an effective amount of an ErbB4 ligand, which can be an agonist ligand or an antagonist ligand depending on the disorder to be treated, to reduce or inhibit GABA release in the subject. Representative disorders that can be treated include, inter alia, autism. By so increasing GABA release, a sedative effective can be induced in the subject.
PCT Patent Application No. WO 2015/095783 A1 by B. Mekonnen et al., disclosed benzodiazepine derivatives, compositions comprising therapeutically effective amounts of those benzodiazepine derivatives and methods of using those derivatives or compositions in treating cognitive impairment associated with central nervous system (CNS) disorders. In particular, it relates to the use of a α5-containing GABAA receptor agonist (e.g., a α5-containing GABAA receptor positive allosteric modulator) in treating cognitive impairment associated with central nervous system (CNS) disorders in a subject in need or at risk thereof, including, inter alia, autism spectrum disorders.
None of the art described above addresses all of the issues that the present invention does, because, regrettably, the aforementioned treatments for autism spectrum and related disorders are mainly symptomatic. They have proven futile in allowing patients to become symptom free, or disorder free. As a result, there is an unmet need in the art for alternative and more effective treatments for autism spectrum disorders and related illnesses.
The present invention relates to methods and regimens of treating autism and autism related spectrum disorders, and more particularly, relates to methods and regimens of administering, through oral dosing, effective amounts of a sub-type selective, positive allosteric modulator (thereafter “PAM”) of the GABAA receptor, zolpidem, or pharmaceutically acceptable salts thereof, and, optionally, in conjunction with other known adjuvant anti-autism therapeutic agents, to treat ASD in humans.